1-beta-arylaminoethyl-2-methyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinolines



United States Patent 3,389,140 1-;9-ARYLAMINOETHYL-Z-METHYL-6,7-DIMETH-OXY-1,2,3,4-TETRAHYDROISOQUINOLINES Thomas A. Montzka, Manlius, N.Y.,assignor to Bristol- Myers Company, New York, N.Y., a corporation ofDelaware No Drawing. Filed May 16, 1966, Ser. No. 550,122 21 Claims.(Cl. 260-286) ABSTRACT OF THE DISCLOSURE l-fl-arylaminoethyl 2methyl-6,7-dimethoxy-l,2,3,4- tetrahydroisoquinolines, wherein aryl issubstituted or unsubstituted phenyl, pyrrolyl, pyridyl, thiazolyl orthienyl are useful as analgesic agents.

This invention relates to a novel series of basic chemicals and theiracid addition salts which are useful analgesic agents, and moreparticularly to certain substituted l-B-arylaminocthyl 2 methyl 6,7dimethoxy-l,2,3,4- tetrahydroisoquinolines.

There is provided by the present invention a member selected from thegroup consisting of compounds of the formula wherein Ar is a memberselected from the group consisting of X X f t s T X X & j-Y and I &Y s Nwherein X and Y are each a member selected from the group consisting ofhydrogen, chloro, bromo, fluoro, trifluoromethyl, nitro, (lower)alkyland (lower)alkoxy, and wherein R is a member selected from the groupconsisting of hydrogen, (lower)alkyl, (lower)alkanoyl,cyclopropylcarbonyl, (lower)alkylsulfonyl and wherein R and R are each amember selected from the group consisting of hydrogen, chloro, bromo,fluoro, trifluoromethyl, nitro, (lower)alkyl and (lower)alkoxy, andnontoxic, pharmaceutically acceptable acid additions salts thereof.

The preferred embodiments of the present invention are the compounds ofthe formulae wherein X and Y have the meaning set forth above and theirnontoxic pharmaceutically acceptable salts, and particularly the fourcompounds (and their salts) of the formulae wherein X is hydrogen orchloro, which are exceptionally eifective analgesic agents.

Included within the present invention are the acid addition saltsprepared by reaction of these basic compounds with organic and inorganicacids such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid,sulfamic acid, glycolic acid, succinic acid, ascorbic acid and the like.

The term (lower)alkyl as used herein refers to straight and branchedchain saturated monovalent aliphatic hydrocarbon radicals having from 1to 10 carbon atoms inclusive, e.g. methyl, ethyl, propyl, iscpropyl,butyl, normal, secondary and tertiary butyl, amyl, decyl, etc.

The compounds of the present invention are prepared as exemplified belowby the reaction of a compound of the formula wherein Ar and R are asdefined above (and preferably a metal salt thereof such as the sodium orpotassium salt) with a reagent of the formula CHaO as illustrated inExample 2 below.

These intermediate quaternary salts are prepared, in one procedure, bythe treatment with alkali, e.g. Na CO of the reaction product of thealcohol of the formula CHaO orrao N OH= CHgCHzOH With SOC12, SOBI'Z,(CH3)2SO4, p-CH C H SO2C1, p-BrC H SO Cl or the like. The anion Z is oflittle consequence in such active intermediates since the chemicalreactivity resides in the cation. The anion Z is defined as an inertanion to exclude unusual anions containing additional substituents, suchas phenolic hydroxyl groups, capable of further reaction with thesequaternary salts. As thus prepared, Z may be chloride, bromide,methanesulfonate, ethanesulfonate, p-toluenesulfonate,p-bromoibenzenesulfonate or the like. By exchange reactions of theconventional type, Z can be replaced by other anions, e.g. phosphate,fluoride, malate, succinate, fumarate, oleate, etc. The salts obtainedthrough these variations of Z may in some cases have special advantagesdue to solubility, ease of crystallization, etc. but these are allsubsidiary to the chemical reactivity of the compound which isindependent of the character of Z The starting materials may be preparedby the methods reported in the literature, e.g., the anilides may beprepared according to Autenrieth, Ber. 34, 3481 (1901); Douglass et al.,J. Am. Chem. Soc. 60, 1486-1489 (1938); De Feoand et al., J. Org. Chem.,28, (10), 2915-17 (1963); Beilstein, Kurbatkow, A., 196, 217; French Patent No. 1,356,497; and Huffman, J. Org. Chem., 23, 727- 9 (1958). Thus,the materials may be prepared by the procedure as exemplified below for3,4-dichloropropionylanilide and 3,4-dichloroethanesulfonylanilide.

CH -CHr-S-Cl CHg-CHz-HI-Cl o T I! NHECHzCHa IfH-C-CH -CHQ An alternateprocedure for the preparation of the compounds of this invention whereinR is hydrogen follows the scheme:

r hydrolysis Clio e.g. 3NHC1 20 CHKO N-CHa 1'13 C Hg-N-A I alkyl-C=Ocrrso CHKO NCH3 CH GI-I -NIL-At An alternate procedure for thepreparation of the compounds of this invention wherein R is methylfollows the scheme:

CHBO H2C=O 1100111 01 NCH3 Another alternate procedure for thepreparation of the compounds of this invention wherein R is methylfollows the scheme:

GHaO

c1130 NCH3 reduction e.g. lithium aluminum hydride CHaO c11 N- 0 H3wherein Ar is as described above.

In a preferred embodiment, the compounds of the present invention areprepared by the reaction of a compound of the formula A1'NHR wherein Arand R are as defined above (and preferably a metal salt thereof such asthe sodium or potassium salt) with a reagent of i the formula X orno q 59 9 038-- orno NCH1 wherein X and Y are each hydrogen, chloro, bromo,fluoro, trifluoromethyl, nitro, (lower)alkyl or (lower) alkoxy. Thisreaction is preferably conducted in an inert, organic solvent, e.g.,dimethylformamide, at a temperature from -l00 C.

The preparation of this reagent is illustrated for the case where X ishydrogen and Y is para-bromo as follows:

CHaO C OQCQ B OHaO C 0 C 115 NHC H=G 01130 C 0 C 9H5 3O CHaO -HC1 OHQONH C HQC 0 2H 3 5 0 1H: 04 orno NH 1 C H: C 0 3C 9H5 -H C1 CHaO N QH3 40C H30 0 2 C 2115 II) 5O -H C1 CHsO N-CH3 H20 II; 0 H 5 5 (III) N OHGOESGB CH30- w 3 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline 1 aceticacid ethyl ester oxalate (I) [A. L. Bluhm and W. J. Gcnsler, J. Org.Chem. 21, 336-339 (1956)].-To a stirred solution of 216.9 g. (1 mole)distilled diethyl a ethoxymethylenemalonate in 1 liter of absoluteethanol was added slowly 181.2 g. (1 mole) of distilledhomoveratrylamine in a nitrogen atmosphere. The reaction mixture wasstirred for 16 hours at room temperature and then concentrated todryness. The resultant oil was taken up in 2 liters of 24% hydrochloricacid, heated on a steam bath for 4 hours and then concentrated todryness to give a yellow oil. This oil was taken up in 1 liter ofabsolute ethanol, filtered to remove insoluble material, saturated withgaseous hydrogen chloride with cooling, stored at room temperature forone day and then concentrated to dryness to give an oil. This wasretaken up in 1 liter of absolute ethanol, saturated with gaseoushydrogen chloride with cooling, stored at room temperature for one dayand again concentrated to dryness. The resultant brown oil was basifiedwith aqueous sodium carbonate, extracted with chloroform, dried oversodium sulfate, and concentrated to an oil which gave a crystallineoxalate with g. of oxalic acid from acetone. One recrystallization fromethanol yielded 228.1 g. (61.7%) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester oxalate. Several recrystallizationsfrom 95% ethanol gave an analytical sample, M.P. 136-164 C. (poorlydefined).

Analysis.Calcd for C15H21NO4'C2H204I C, H, 6.26; N, 3.79. Found: C,55.28; H, 6.25; N, 3.81.

6,7 dimethoxy Z-methyl-1,2,3,4-tetrahydroisoquinolined-acetic acid ethylester hydrochloride (II) [A. Brossi et al., Helv. Chim. Acta, 43,583-593 (1960)].To 3.8 g. (0.0135 mole) of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl ester,obtained from the oxalate by neutralization with sodium carbonate, wasadded 1.2 ml. of 40% formaldehyde and 3.6 ml. of 88% formic acid. Thereaction mixture was heated on a steam bath for 2 hours. Three ml. of 6N hydrochloric acid were added and the solution was concentrated todryness to yield 4.5 g. of crude crystalline 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-l-acetic acid ethyl esterhydrochloride. One recrystallization from absolute ethanol gaveanalytical material, M.P. 179-183 C.

Analysis.-Calcd for C H NO.,-HCl: C, 58.26; H, 7.34; N, 4.25. Found: C,58.36; H, 7.38; N, 4.32.

6,7 dimethoxy l fi-hydroxyethyl-Z-methyl-1,2,3,4- tetrahydroisoquinolinehydrochloride (III).-To a stirred suspension of 7.6 g. (0.2 mole) oflithium aluminum hydride in 100 ml. of tetrahydrofuran was added slowly58.5 g. (0.2 mole) of 6,7-dimethoxy-2-methyl-1,2,31,4-tetrahydroisoquinoline-l acetic acid ethyl ester (obtained from thehydrochloride by neutralization with sodium carbonate) in ml. oftetrahydrofuran. The suspension was refluxed for 4 hours. Twenty-fiveml. of water were cautiously added and the suspension was stirred withwarming until white. Anhydrous sodium sulfate was added and the solidsremoved by filtration. The filtrate was concentrated to dryness to give49.9 g. (99.3%) of an oil which gave crystalline6,7-dimethoxy-l-fi-hydroxyethyl 2 methyl 1,2,3,4 tetrahydroisoquinolinehydrochloride from acetone. One recrystallization from absolute ethanolyielded 42.6 g. of analytical material, M.P. 179- 182 C.

Analysisr-Calcd for C H NO -HCI: C, 58.43; H, 7.71; N, 4.87. Found: C,58.26; H, 7.88; N, 4.77.

[2,1 a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoliniump bromobenzenesulfonate (IV).- To a stirred solution at room temperatureof 5.3 g. (.021 mole) of 6,7-dimethoxy-1-p-hydroxyethyl-Z-methyl-1,2,3,4-tetrahydroisoquinoline (obtained from the hydrochloride byneutralization with sodium carbonate) in 100 ml. of chloroform was added5.5 g. (.0216 mole) of p-bromobenzenesulfonyl chloride. Stirring wascontinued for 4 hours. Anhydrous sodium carbonate (11.2 g.) was addedand stirring was continued for 16 hours. The mixture was filtered andthe filtrate concentrated to give 9.6 g. (97%) of crude crystallinematerial. Several recrystallizations from isopropanol yieldedanalytically pure [2,1-a]azetidino 6,7 dimethoxy 2methyl-1,2,3,4-tetrahydroisoquinolinium p-bromobenzenesulfonate, M.P.182484.5" C.

Analysis.-Calcd for'C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C,51.01; H, 5.29; N, 2.92.

As its fumarate salt, the preferred compound present invention has thestructure C 11 CHQO \2-0113 cinorn-n -ci or C n;

C II:

and may be named 1-(N-propionyl-3,4-dichloroanilinoethyl) 6,7dimethoxy-Z-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride or 1 [,0(N-propionyl-3,4-dichloroanilino)ethyl] 6,7dirnethoxy-2-methyl-1,2,33,4- tetrahydroisoquinoline dihydrochloride.This compound was tested for analgesic activity by the phenylquinonetest of Sigmund et al., Proc. Soc. Exptl. Biol. and Med, 95, 729 (1957)in which an analgesic reduces the induced writhing of the mice. Atdosages of 100 and 50 mgrrL/kg. p.o. in mice given 50 minutes before thephenyl-p quinone is injected, the reduction in induced writhing at theend of the first hour was found to be 100 and 67% respectively for thiscompound. This compound was also shown to be a potent analgesic by thestandard rat-tail flick test.

The following examples are intended to illustrate the inventiondescribed herein without unduly restricting it.

Example 1.-Preparation of 3,4-dichloroethanesulionylanilide To 16.2 g.(0.1 mole) 3,4-dichloroaniline suspended in 250 ml. of water was added8.4 ml. of 12 N hydrochloric acid. When complete solution was achieved,it was decolorized with charcoal. To the clear solution was added 12.9g. (0.1 mole) ethane sulfonyl chloride followed immediately by 18.5 g.of sodium acetate in 50 ml. of water. The resulting suspension wasstirred for 2 hours.

The colorless crystals were collected by filtration and washedthoroughly with water. One recrystallization from 95% ethanol gave 3.4g. (14%) of crystalline 3,4-dichloroethanesulfonylanilide, M.P.117.5-118.5 C.

Analysis.-Calcd for C H CI NO S: C, 37.81; H, 3.57; N, 5.74. Found: C,38.00; H, 3.64; N, 5.47.

Example 2.Preparation of p-fiuoroethanesulfonanilide A stirred solutionof 11.4 g. (0.068 mole) p-fluoroaniline hydrochloride in 100 ml. waterwas treated with 9.6 g. (0.068 mole) ethanesulfonyl chloride and 11.8 g.pyridine. After 15 minutes, the mixture was cooled and the crystalscollected. These were recrystallized from aqueous ethanol to yield 5.7g. (42%) pure p-fluoroethanesulfoanilide, M.P. 69.5-70.5 C.

/l1ml -'sis.--Calcd for C H FNO S: C, 47.22; H, 4.96; N, 6.98. Found: C,47.41; H, 5.02; N, 7.18.

of the 8 Example 3.Preparation of 6,7-dimethoxy 1 5 (N-ethanesulfonyl-p-chloroanilino)ethyl-Z-methyl 1,2,3,4-tetrahydroisoquinoline To a stirred solution of 1.2 g. (0.0055 mole)p-chloroethanesulfonylanilide in 25 ml. of dried dimethylformamidemaintained under a nitrogen atmosphere was added 0.23 g. of a 5 8.6%dispersion of sodium hydride in mineral oil. After 15 minutes, 2.35 g.(0.005 mole) [2,1-a] azetidino-6,7-dimeth0xy-2-methyl-1,2,3,4tetrahydroisoquinolinium p-bromobenzenesulfonate was added, and stirringwas continued for 24 hours.

The solution was concentrated under reduced pressure to give a solidresidue. This was suspended in water and extracted three times with 2550m1. portions of ethyl acetate. The combined ethyl acetate extracts weredried over MgSO filtered, and concentrated. The resultant oil was takenup in acet-onitrile and washed with n-pentane to remove mineral oil. Theacetonitrile solution was concentrated to give 2.2 g. of an oil whichcrystallized upon scratching. One recrystallization from absoluteethanol gave 0.9 g. (40%) of colorless crystalline material, 6,7-dimethoxy 1-5-(N-ethanesulfonyl-p-chloroanilino)ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline, M.P. 96.5 C.

AnaZySis.-Calcd for C22H29C1N204S: C, H, 6.45; N, 6.18. Found: C, 57.99;H, 6.47; N, 6.03.

By similar procedures, the compounds of the following Examples 4 through14 were prepared in the indicated amounts and with the propertiesstated.

Example 4.Preparation of 6,7-dimethoxy 1 3 (N-ethanesulfonyl-p-fiuoroanilino)ethyl-Z-methyl 1,2,3,4-tetrahydroisoquinoline H; 0.23 g. sodium hydride (58.6% dispersion) 1.12g. (0.005 mole) p-fluoroethanesulfonylanilide 2.35 g. (0.005 mole)[2,1-a]azetidino-6,7-dimethoxy-2- methyll,2,3,4-tetrahydroisoquinoliniutn-p-bromobenzenesulfonate yielded 0.9 g.(41.4%)6,7-dimethoxy-l-fi-(N-ethanesulfonyl-p-fiuoroanilino)ethyl-2-methyl-1,2,3,4tetrahydroisoquinoline from absolute ethanol, M.P. 99-101 C.

Analy.ris.Calcd for C H FN O S: C, 60.53; H, 6.70; N, 6.42. Found: C,60.57; H, 7.03; N, 6.74. Example 5.Preparation of6,7-dimethoxy-l-fi-(N-ethane sulfonylanilino)ethyl 2 methyl 1,2,3,4tetrahydroisoquinoline hydrochloride hemiethanolate 9 0.23 g. sodiumhydride (58.6% dispersion) 1.02 g. (0.005 mole) ethanesulfonylanilide2.35 g. (0.005 mole) [2,1-a] azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinnium-p-bromobenzenesulfonateConcentration of the acetonitrile solution gave 2.0 g. of oily material.This material was taken up in 25 ml. of isopropanol and 2 ml. of 6 Nhydrochloric acid was added. The solution was concentrated to dryness togive a crystalline material. Recrysallization from 95% ethanol yielded1.45 g. (63%) 6,7-rii-methoxy-l- 8-(N-ethanesulfonylanilino)ethy1-2-methyl-1,2,3,4-tetrahydroisoquin0line hydrochloridehemiethanolate as a white crystalline material, M.P. 160.5-163.5 C.

Analysis.-Calcd for C H N O -HCl /2C H O: C, 57.78; H, 7.17; N, 5.86.Found: C, 57.48; H, 7.32 N, 5.91. Example 6.Preparation of6,7-dimethoxy-1-fl-(N-ethanesulfonyl p methylanilino)ethyl 2 methyl 1,2,

3,4 tetrahydroisoquinoline 0.23 g. sodium hydride 8.6% dispersion) 1.1g. (0.005 mole) p-methylethanesulfonylanilide 2.35 g. (0.005 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-l,2,3,4-tetrahydroisoquinolinium-p-bromobenzenesulfonate yielded1.4 g. (67%) 6,7-dimeth0Xy-1-B-(N-ethanesulfonyl p methylanilino)ethyl 2methyl 1,2,3,4 tetrahydroisoquinoline from absolute ethanol, M.P. 95-96C. Analysis.-Calcd for C H N 0 S: C, 63.87; H, 7.46;

N, 6.48. Found: C, 64.01; H, 7.54; N, 6.65.

Example 7.--Preparation of 6,7-dimethoxy-1-/3-(N-propionyl pchloroanilino)ethyl 2 methyl 1,2,3,4- tetrahydroisoquinoline 0.7 g.sodium hydride (58.6% dispersion) 2.9 g. (0.015 mole)pchloropropionylanilide 7.05 g. (0.015 mole) [2,1-a]azetidino-6,7-dimethoxy-2- methyl-l,2,3,4tetrahydroisoquinolinium-p-bromobenzenesulfonate yielded 4.5 g. (72.3%)6,7-dimethoxy-1-B-(N-popionylp chloroanilino)ethyl 2 methyl 1,2,3,4tetrahydroisoquinoline from absolute ethanol, M.P. 84.5-85.5 C.Analysis.-Calcd for C H ClN O C, 66.25; H, 7.01;

N, 6.72. Found: C, 66.39; H, 7.07; N, 6.60.

Example 8.-Preparation of 6,7-dimethoxy-1-fi-(N-propionyl 3,4dichloroanilino)ethyl 2 methyl 1,23,4- tetrahydroisoquinoline fumarate'CHaO -C4H4 4 OHHO N-CH:

(EHgCHg-N -C1 C] I CH3 10 0.23 g. sodium hydride (58.6% dispersion) 1.2g. (0.005 mole) 3,4-dichloropropionylanilide 2.3 5 g. (0.005 mole)[2,l-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoliniurri-p-hromobenzenesulfonateConcentration of the acetonitrile solution gave 2.3 g. of a red oil. Theoil was taken up in ml. of methanol and 0.28 g. of fumaric acid wasadded. This was warmed gently until all of the fumaric acid went intosolution. Ethyl acetate (10 ml.) was added and the fumarate saltcrystallized upon standing. Recrystallization from methanol-ethylacetate yielded 0.9 g. (31%) of 6,7 dimeth- 'OXY 1 B (N propionyl 3,4dichloroanilino)ethyl- 2-methyl-1,2,3,4-tetrahydroisoquinoline fumarate,M.P. l52-153.5 C.

Analysis.Calcd for C23H28C12N203'C4H404: C, 57.14; H, 5.70; N, 4.94.Found: C, 56.95; H, 5.84; N, 4.84. Example 9.--Preparation of6,7-dimethoxy-1-fi-(N-propionyl p fluoroanilino)ethyl 2 methyl 1,2,3,4-

tetrahydroisoquinoline 0.23 g. sodium hydride (58.6% dispersion) 0.92 g.(0.005 mole) p-fiuoropropionylanilide 2.315 g. (0.005 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium-p-bromobenzenesulfonate yielded1.0 g. (50%) 6,7-dimethoxy -1-,3-(N-propionyl-pflu0roanilino)ethyl 2methyl 1,2,3,4 tetrahydroisoquinoline from absolute ethanol, M.P.126127.5 C.

Analysis.--Calcd for C H FN O C, 68.97; H, 7.30; N, 7.00. Found: C,69.16; H, 7.59; N, 7.34.

Example 10.-Preparation of 6,7-dimethoxy-1-fl-(N-propionylanilino)ethyl2 methyl 1,2,3,4 tetrahydroisoquinoline CHaO CHaO H3 1.23 g. sodiumhydride (58.6% dispersion) 4.1 g. (0.025 mole) propionylanilide 11.8 g.(0.025 mole) [2,l-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoliniurn-pbromobenzenesulfonate yielded6.3 g. (66%) 6,7-dimethoxy-1-fi-(N-propiony1- anilino) ethyl 2 methyl1,2,3,4 tetrahydroisoquinoline from absolute ethanol, M.P. IOU-101 C.

Analysis.-Calcd for C H N O C, 72.22; H, 7.91; N, 7.33. Found: C, 72.32;H, 7.89; N, 7.53.

1 1 Example 11.Preparation of 6,7-dimethyl-l-fl N-propionyl pmethylanilino)ethyl 2 methyl 1,2,3,4- tetrahydroisoquinoline fumarate0.23 g. sodium hydride (58.6% dispersion) 0.9 g. (0.005 mole)p-methylpropionylanilide 2.35 g. (0.005 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium-pbromobenzenesulfonateConcentration of the acetonitrile solution gave 2.0 g. of a yellow oil.The oil was taken up in ml. of methanol and 0.28 g. of fumaric acid wasadded. This was warmed gently until all of the fumaric acid went intosolution. Ethylacetate (10 ml.) was added and the fumarate saltcrystallized upon standing. Recrystallization from methanol-ethylacetate yielded 0.9 g. 6,7-dimethoxy- 1 9 (N propionyl pmethylanilino)ethyl 2 methyl-l,2,3,4-tetrahydroisoquinoline fumarate,MP, 154 155.5" C.

Analysis.Calcd for C H N O -C H O C, 65.60;

H, 7.08; N, 5.47. Found: C, 65.77; H, 7.23; N, 5.72.

Example l2.-Preparation of 6,7 dimethoxy 1 ,8 (N- acetyl 3,4dichloroanilino)ethyl 2 methyl 1,2,3, 4-tetrahydtroisoquinoiline oxalate0.38 g. sodium hydride (58.6% dispersion) 1.6 g. (0.0075 mole)3,4-dichloroacetylanilide 3.6 g. (0.0075 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium-pbromobenzenesulfonateConcentration of the acetonijtrile solution gave 3.3 g. of a yellow oil.The oil gave a crystalline salt with 0.66 g. of oxalic acid from acetone(30 ml). Recrystallization from 95% ethanol yielded 2.0 g. (51%)6,7-dimethoxy- 1 B (N acetyl 3,4 dichloroanilino)ethy1 2 methyl 1,2,3,4tetrahydroisoquinolirie oxalate, M.P. 159- 161 C.

Analysis.Calcd for C22H25C12N203C2H204: C, 54.65; H, 5.35; N, 5.31.Found: C, 54.62; H, 5.62; N, 5.20.

Example 13.-Preparation of 6,7 dimethoxy 1 B (N- cyclopropylcarbonyl 3,4dichloroanilino)ethyl 2- methyl-1,2,3,4-tetrahydroisoquinoline oxalate0.23 g. sodium hydride (58.6% dispersion) 1.8 g. (0.0075 mole)3,4-dichlorocyclopropanecarbonylanilide 3.6 g. (0.0075 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tctrahydroisoquinolinium-pbromobenzenesulfonateConcentration of the acetonitrile solution gave 3.5 g. of

an orange oil. The oil gave a crystalline salt with 0.68 g.

of oxalic acid from acetone (30 ml.). Recrystallization from ethanolyielded 28 g. (78%) 6,7-dimethoxy- 1 5 (N cyclopropylcarbonyl 3,4dichloroanilino) ethyl 2 methyl 1,2,3,4-tetrahydroisoquinoline oxalate,

MP. 177-179 C.

56.42; H, 5.46; N, 5.06. Found: C, 56.53; H, 5.79; N,

Example 14.Preparation of 6,7 dimethoxy 1 B (N- formyl 3,4dichloroanilino)ethyl 2 methyl 1,2,3, 4 tetrahydroisoquinoline fumarate1.2 g. sodium hydride (58.6% dispersion) 5.0 g. (0.0261 mole)3,4-dichloroformylanilide 11.2 g. (0.0238 mole)[2,1-a]azetidino-6,7-dimethoxy-2-methyl-1,2,3,4-tetral1ydroisoquinolinium-p-bromobenzenesulfonateConcentration of the acetonitrile solution gave 10.0 g. of an oil. Theoil was taken up in ml. of acetone and 2.7 g. of fumaric acid was added.This was warmed gently until all of the fumaric acid went into solution.The solution was cooled to room temperature, seeded and the fumaratesalt crystallized upon standing. Recrystallization from 95 ethanolyielded 9.6 g. (75%) 6,7 dimethoxy 1 B (N formyl 3,4dichloroanilino)'ethyl 2 methyl 1,2,3,4 tetrahydroisoquinoline fumarate,Ml. 187-191 C.

A7lal)SiS.-C3.1Cd fOI' C21H24Cl2N203 ci flq ol l 55.66; H, 5.23; N,5.19. Found: C, 55.68; H, 5.35; N, 5.00.

xample 15.-Preparation of l-B-(pchloroanilino)ethyl- 6,7 dimethoxy 2methyl 1,2,3,4 tetrahydroisoquinoline dihydrochloride hemihydrate Asolution of 3.6 g. (0.00864 mole) 6,7-dimethoxy- 2 methyl 1 i9 (Npropionyl p chloroanilino) ethyl-1,2,3,4 -tetrahydroisoquinoline in 30ml. of 3 N hydrochloric acid (0.09 mole) was heated on a steam bath for3 hours. The solution was then concentrated to dryness to leavecolorless crystalline material. One recrystallization from 95 ethanolgave 3.1 g. (81.5%) ofl-fi-(p-chloroanilino)ethyl-6,7-dimethoxy-Z-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride hemihydrate, M.P. -175 C.

Analysis.-Calcd for C, 54.25; H, 6.37; N, 6.33; E 0, 2.03. Found: C,54.25; H, 6.33; N, 6.02; H O, 2.31,

By similar procedures, the compounds of the following examples, Examples16 through 19, were prepared in the indicated amounts and with theproperties stated.

13 Example I6.Preparation of6,7-dimethoxy-1-B-(3,4-dichloroanilino)ethyl 2 methyl1,2,3,4-tetrahydroisoquinoline dihydrochloride CHQO morn-amQ-m 6,7dimethoxy 1 ,8 (N propionyl-3,4-dichloroanilino) ethyl 2 methyl1,2,3,4-tetrahydroisoquinoline fumarate (5.8 g., 0.01 mole) wasneutralized with Na CO extracted with methylene chloride andconcentrated to form the free base. Use of the free base in theprocedure of Example 15 yielded 4.0 g. (85.6%) 6,7-dimethoxyl-,B-(3,4-dichloroanilino)ethyl-2-methyl-l,2,3, 4-tetrahydroisoquinolinedihydrochloride from 95% eth anol, M.P. 155.5-l60.5 C.

Analysis.Calcd for C H Cl N O -2HCl: C, 51.30; H, 5.60; N, 5.98. Found:C, 51.22; H, 5.63; N, 5.75. Example l7.--Preparation of6,7-dimethoxy-l-B-(4-fluoroanilino)ethyl 2 methyl l,2,3,4tetrahydroisoquinoline dihydrochloride CHaO CHaO

YHNHPNH J Use of 6,7 dimethoxy-14i-(N-propionyl-p-fluoroanilino) ethyl 2methyl 1,2,3,4-tetrahydroisoquinoline (4.6 "g., 0.115 mole) in theprocedure of Example 15 yielded 305 g. (77%)6,7-dimethoxy-1-,B-(4#fluoroanilin0) ethyli- 2 methyl 1,2,3,4tetrahydroisoquinoline dihydrochloride from 95% ethanol, M.P. 150-210 C.

Analysis.Calcd for C H FN O '2HCl: C, 57.55; H, 6.52; N, 6.71. Found: C,57.52; H, 6.67; N, 6.65.

Example l8.-Preparation of 6,7-dimethoxy-l-fl-(anilino) ethyl 2 methyl1,2,3,4 tetrahydroisoquinoline dihydrochloride CHaO UHsO

CHsO

CHKO

Qtom-NHG-om 6,7 dimethoxy 1 [3 (N-propionyl-p-methylanilino)ethy1-2-methyl-1,2,3,4-tetrahydroisoquinoline oxalate (6.6 g., 0.013mole) was neutralized with Na CO extracted with ethyl acetate andconcentrated to form the free base. Use of the free base in theprocedure of Example 15, yielded 3.1 g. (57.5%) 6,7-dimethoxyl-fl-(4-methylani- CHaO 14 lino)ethyl 2 methyl1,2,3,4-tetrahydroisoquinoline dihydrochloride hemihydrate from ethanol,M.P. 167- 176 C.

Analysis.Calcd for C H N O -2HCl /2H O: C, 59.71; H, 7.40; N, 6.63.Found: C, 59.72; H, 7.39; N, 6.76.

Example 20.--Preparation of 6,7-dimethoxy-2-methyl-1- ,8 (N methyl pchloroanilino)ethyll 1,2,3,4 tetrahydroisoquinoline dihydrochloridemonohydrate CHsO To the free base of 3.1 g. (0.007 mole)l-/8p-chloroanilino ethyl 6,7 dimethoxy 2 methyl1,2,3,4-tetrahydroisoquinoline dihydrochloride hemihydrate prepared byneutralization with sodium carbonate and extraction with methylenechloride was added 0.6 ml. of 40% formaldehyde solution and 1.7 ml. of88% formic acid. The resultant solution was heated on a steam bath for 2hours. Two ml. of 12 N hydrochloric acid was added and the solution wasconcentrated to dryness to give crystalline material. Onerecrystallization from 95% ethanol gave 0.7 g. (22%) of6,7-dimethoxy-2-methyl- 1fl-(N-methyl-p-chloroanilino)ethyl-1,2,3,4-tetrahydroisoquinolinedihydrochloride monohydrate, M.P. 147- 159 C.

Analysis.-Ca1cd for C H ClN O -2l-ICl-H O: C, 54.14; H, 6.68; N, 6.01; HO, 3.94. Found: C, 53.94; H, 6.44; N, 6.28; H O, 4.00.

By similar procedures, the compounds of the following Examples 21through 22 were prepared in the indicated amounts and with theproperties stated.

Example 21.Preparation of 6,7 dimethoxy l-p-(N- methyl 4fiuoroanilino)ethyl 2-methyl-1,2,3,4-tetrahydroisoquinolinedihydrochloride OHaO CHaO

CH O

Use of 6,7-dimethoxy-1 3 (p-methylanilino)ethyl-2- methyl 1,2,3,4tetrahydroisoquinoline dihydrochloride (2.3 g., 0.00545 mole) in theprocedure of Example 20 yielded 0.7 g. (29.6%)6.7-dimethoxy-l-fi-(N-methyl-pmethylanilino) ethyl 2 methyl 1,2,3,4tetrahydroisoquinoline dihydrochloride from absolute ethanol, M.P.150170 C.

15 Analysis.-Calcd for C I-I N O -2HCl: C, 61.82; H, 7.55; N, 6.56.Found: C, 61.64; H, 7.77; N, 6.24.

Example 23 .Preparation of 6,7-dimeth0xy 1 B (N-methyl-3,4-dichloroanilino)ethyl 2 methyl 1,2,3,4-tetrahydroisoquinoline dihydrochloride A stirred suspension of lithiumaluminum hydride (0.46 g., 0.012 mole) in 20 ml. tetrahydrofuran wastreated slowly with a solution of 6,7-dimethoXy-1B-(N-formyl-3,4-dichloroanilino)ethyl-Z-methyl 1,2,3,4-tetrahydroisoquinoline(free base obtained from fumarate salt by neutralization with potassiumcarbonate) (2.54 g., 0.006 mole) in 20 ml. tetrahydror'uran. After atwo-hour reflux, 1 /2 ml. water was cautiously added, and the mixturestirred until the salts were completely white. Anhydrous sodium sulfatewas added, and the solids removed by filtration. Concentration of thefiltrate gave an oil which gave a crystalline hydrochloride fromacetone-dry hydrogen chloride. Recrystallization from isopropanol thenethanol gave the product, 6,7-dimethoxy-l-B-(N-methyl-3,4-dichloroanilino)ethyl-Z-methyl 1,2,3,4-tetrahydroisoquinolinedihydrochloride (1.2 g., 49%), M.P. 127-139 C.

Analysis.-Calcd for C H Cl N O C, 52.30; H, 5.85; N, 5.81. Found: C,52.00; H, 5.99; N, 5.60.

Example 24 When, in the procedure of Example 2,p-chloroethanesulfonylanilide is replaced by an equal molar amount ofp-trifluoromethylethanesulfonylanilide, 3,4dichloropropanesulfonylanilide, p-bromoethanesulfonylanilide,p-methoxyethanesulfonylanilide, 2-ethylsulfonylaminopyridine,2-ethylsulfonylaminothiazole, Z-ethylsulfonylaminothiophene,5-chloro-2-ethylsulfonylaminothiazole, 3-ethylsulfonylaminopyrrole,p-bromopropionylanilide, 2,6-dichloropropionylanilide,2,4-dichloropropionylanilide,

3 ,4-dichlorobutyrylanilide, p-rnethoxybutyrylanilide,p-trifluoromethylpropionylanilide, o-trifiuoromethylpropionylanilide,m-trifluoromethylpropionylanilide, p-is0propylpropionylanilide,2-propionylaminopyridine, 4-propionylaminopyridine,2-propionylaminothiazole, 2-propionylaminothiophene,3-propionylaminothiophene, 2-chlor0-3-propionylaminothiophene,

3 -chloro-2-propionylaminothiophene, 4-chlor0-2-propionylaminothiazole,5-trifluoromethyl-2-propionylaminothiazole,S-chloro-2-propionylaminothiazole, 3-propionylan1inopyrrole,2-propionylaminopyrrole, 3-chloro-4-propionylaminopyrrole,2,6-dichloro-4-propionylaminopyridine,4,5-dichloro-2-propionylaminothiazole,2,3-diehloro-4-propionylamin0thiophene,2,3-dichloro-4-propionylamin0pyrrole, cyclopropanecarbonylanilide,p-chlorocyclopropanecarbonylanilide,p-methylcyclopropanecarbonylanilide,

'1 6 o-chlorocyclopropanecarbonylanilide,p-bromoeyclopropanecarbonylanilide,2,4-dichlorocyclopropanecarbonylanilide,2,6-dichlorocyclopropanecarbonylanilide,p-trifiuoromethylcyclopropanecarbonylanilide,p-methoxycyclopropanecarbonylanilide,4-cyclopropy1carbonylaminopyridine, 2-cyclopropylcarbonylaminothiazole,3-cyclopropylearbonylaminothiophene, 2-cyclopropylcarbonylaminopyrrole,4-trifiuoromethylaniline,

3 -trifiuoromethylaniline, Z-trifiuoromethylanih'ne,2,4-dichloroaniline,

4-br0moaniline,

2,6-dichloroaniline,

Z-aminopyrrole,

4-aminopyridine,

3-aminothiophene,

3 ,4-dichloromethane anilide,

4-fluoromethaneanilide,

methylanilide,

phenylanilide,

p-chlorophenylanilide,

3 ,4-dich1oro-N-phenylanilide,

4-trifluoromethyl-N-phenylanilide,

4-chloro-N-phenylanilide,

p-trilluoromethylphenylanilide,

propylanilide,

isopropylanilide,

3 ,4-dichloropropylanilide,

3 ,4-dichloroethylanilide,

butylanilide,

p-metylphenylanilide,

o-methoxyphenylanilide,

m-nitrophenylanilide,

p-fluorophenylanilide, and

p-bromophenylanilide,

there are obtained,

6,7-dimethoxy-1-[i- (N-ethanesulfonyl-p-trifiuoromethylanilinoethyl-Z-methyll ,2,3 ,4-tetrahydroisoquinoline,

6,7-dimethoxy- 1 -fl- N pro panesulfonyl-3,4-dichloroanilino)ethyl-2-methyl-1,2,3 ,4-tetrahydroisoquinoline,

6,7-dimethoXy-1-p- (N-ethanesulfonyl-p-bromoanilino)ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-1-,8-(N-ethanesulfonyl-p-methoxyanilino)ethyl-2-methy1-1,2,3,4-tetrahydroisoquinoline,

6,7 -dimethoxy- 1 8- N-ethylsulfonyl-N-Z-pyridinoamino)ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-143-(N-ethylsulfonyl-N-Z-thiazolylaminoethyl-2-methyl-1,2,3 ,4-tetrahydroisoquinoline,

6,7-dimethoxy-1 -,8- (N-ethylsulfonyl-N-Z-thieny1amino)ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-1- 8-(N-ethylsulfonyl-N-5-chloro-2- thiazolylamino)ethyl-Z-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7 -dimethoxy- 1-;9- N-ethylsulfonyl-N-3-pyrrolylamino) ethyl-2-methyl-1,2,3 ,4-tetrahydroisoquinoline,

6,7-dimethoXy-1- 3-(N--propionyl-p-bromoani1ino) ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoXy-1-fi- (N-propionyl-2,6-dichl0roanilino)ethyl-2-methyl-1,2,3,4-tetrahydr0isoquinoline,

6,7-dimethoxy-1 9-(N-propionyl-2,4-dichloroanilino)ethyI-Z-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-1-5- (Nbutyryl-3,4-dichloroanilino)ethyl-2-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-l- 3- (N=butyryl-p-methoxyanilino ethyl-2methy1-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoXy-113-(N-propionyl-p-trifluoromethylanilinoethyl-2-n1ethy1-1,2,3 ,4-tetrahydroisoquinoline,

6,7-dimethoxy-1-[3- (N-propionyl-o-trifiuoromethylanilino)ethyI-Z-methyl-1,2,3,4-tetrahydroisoquinoline,

6,7-dimethoxy-1-B-(N-propionyl-m-trifiuoromethylanilino ethyI-Z-methyl-1, 2,3 ,4-tetrahydroisoquinoline,

6,7-dimeth0xy-1-fi- (N-propionyl-p-isopropylanilino) ethyl-Z-methyl- 1,2,3,4-tetrahydroisoquinoline,

20 PREPARATION OF RESOLVING AGENTS Example 1 -2-nitrotartranilic acid.()-2,3-diacetylsuccinic anhydride (44 g., 0.2 mole) and 2-nitroaniline(35 g., 0 O 0.25 mole) were placed with 300 ml. methylene chloride II IIand heated under reflux for 3 /2 hours. This solution was HO' C '?H (|3HC NH Br cooled to room temperature and treated dropwise with 0H 0Hstirring with a solution of 39 g. potassium hydroxide (86% 0 O pellets;0.6 mole) in 400 ml. water. This was stirredone H g hour at roomtemperature. The layers Were separated and the methylene chloride layerwas extracted with 100 ml. 4m )H more water. The combined aqueous layerswere heated on a steam bath, treated with decolorizing carbon, filteredhot through diatomaceous earth (Celite), acidified HO(CH-CH-C-NH with 50ml. concentrated hydrochloric acid and cooled 6 6 at 5 overnight. Thecrystals were collected and washed (El with 100 ml. cold Water to yield32 g. yellow crystals. This material was taken up in 300 ml. hot water,treated and then the resohled mtenpedlates accordmg to with 15 ml.concentrated hydrochloric acid and cooled. the method Prevlouslydescnbiad herem' Collection of the crystals gave 28 g. (52%) of 2-nitroidextromtatory substltuted tartramllc ands tartranilic acid. A sample wasrecrystallized from n-prosolving agents are prepared by the consecutivesteps ot: panel for analysis, M'P' [0511325 1 +7150 (a) Heating amlxture of (+)-2,3-d1acety1-succmic (9:25, ethanol), [0511325 +8930 (c:083 H2O) anhydride or its functional equivalent as an acylating forC10H10N2O7: C, 4445; H, 373; agent for primary amines and an aniline,and preferably N, 1037 Found. c, 44.41; H, 3.79; N 1031 a substitutedaniline having the formula Example 2 HQN --1t(+)-2,4-dichlorotartranilic acid.( +)-2,3-diacetylsuc- 3O cinicanhydride (22 g., 0.1 mole) and 2,4-dichloroaniline (18 g., 0.11 mole)in 150 ml. methylene chloride were stirred together for two hours. Asolution of 21 g. potaswherein R and R have the meaning set out above,to Sillm hydroXide P H1016) in 200 water produce the correspondingdiacetyl-tartranilic acid, and r s addfid and the two-Phase SystemStirred vigorously (b) Deacetylating said diacetyl-tartranilic acid byfor one hour. The methylene chloride layer was separated, treatment withalkali to produce the desired dextro-roc ed W th 1 0 ml. Water anddiscarded. The comtatory t t ili id, bined aqueous extracts were warmedon a steam bath, The resolution of the6,7-dimethoxyl-l-fi-hydroxyethylfiltered, acidified with 35 ml.concentrated hydrochloric 2-methyl-1,2,3,4-tetrahydroisoquinolinedescribed above acid and cooled for crystallization. Collection of thiscompn'ses; 4O material gave 17 g. (59%) colorless (+)-2',4'-dichloro- Fi i t f h t ti i lt tartranilic acid. Several crystallizations fromwater gave of said amine with a dextro-rotatory ring-substituted tarananalytical p 10 tranilic acid, said substituent comprising preferably at95% ethanol)- least one nitro, chloro or bromo group, y for m s s C,4034; 3.08;

(b) Separating said enantiomeric salts by fractional Found: cstallization and then (c) Converting said separated enantiomeric saltsto Example 3 the respective optical isomers of the organic amine,prefer- (+)-2,3-diacetoxysuccinic anhydride.--A mixture of ably bytreatment with a strong base. tartaric acid (150 g., 1 mole) in 700 ml.acetic an- The (+)-2,3-diacetylsuccinic anhydride used as a starthydridewas warmed with stirring until the exothermic ing material is preparedaccording to Organic Syntheses, reaction started. Heating wasdiscontinued and the reac- Collected Volume IV, page 242, Wiley (1963)or prefertion was allowed to run its course (about 2-3 hours). ably asexemplified below. It is apparent that it can be The colorless solutionwas concentrated to dryness at replaced by the corresponding mono-acidhalides or W reduced pressure. Final drying under high vacuum gavemono-mixed anhydrides and other functional equivalents a quantitativeyield of (+)-2,3-diacetoxysuccinic anhyfor the acylation of anilines.dride (216 g.) of good purity. This material may be re- The followingexamples are given to illustrate the crystallized from ethylacetate--Skellysolve B" if betpreparation of the resolving agents andthe preparation ter purity is desired. Recrystallized material has ameltof the optical isomers of the compounds of this invention. ing pointof 133.0-133.5 and +60.5 (c.=6.2 All temperatures are given in degreesCentigrade. acetone).

0 X IIC CCH-CH- NH- 6H 6H Y X, Y Cryst. solvent; [a]D (C) 1 V (a- Yield,

M.P., 0. Percent Va 2-NO2 H20 (H01) 2 +s9.s (0.8, H20)..." 196.0198.0 50Vb 2,4-diCL- H2O or HOAc +10o.7 (1.6) 1825-1925 59 241.. I120 +994(1.6)-- 182.5 47 4-01... Ethanol-H20- +l08.9 (1 e)- 5. 0 as 4-Br(hydrate) Ethanol-H20 .5 (l. .5 e7

1 Unless otherwise indicated rotations were taken in ethanol.

Z This material sometimes crystallizes containing -25% potassium salt.Recrystallization from dilute HCl converts to acid.

3 This material tends to form a gel on recrystallization. It isrecommended that it not be recrystallized.

Substituted tartranilic acids V (a-e).--(+)-2,3-diacetoxysuccinicanhydride, (21.6 g., 0.1 mole) and substituted aniline (0.11 mole) in200 ml. methylene chloride were heated under reflux for 3 hours. Thissolution was treated with a solution of potassium hydroxide (21 g. of86% potassium hydroxide pellets; 0.32 mole) in 200 ml. water and stirredvigorously for minutes. The methylene chloride layer was separated andextracted with 100 ml. water. The combined aqueous layers were stirredfor 2 hours, then warmed to solution, treated with decolorizing carbon(if necessary), filtered through diatomaoeous earth (Celite), acidifiedwith 35 ml. concentrated hydrochloric acid and cooled immediately forcrystallization. The crystals were collected, washed with water, andthen recrystallized from the indicated solvent.

Example 4 -2-chlorotartranilic acid.( -2,3-diacetoxysuccinic anhydride(21.6 g., 0.1 mole) and 2-chloroaniline (12.8 g., 0.1 mole) in 100 ml.methylene chloride were heated under reflux for one hour. This solutionwas treated with a solution of potassium hydroxide (22 g., 86% pellets;0.32 mole) and the methylene chloride was removed under reducedpressure. The remaining aqueous solution was heated on a steam bathminutes, filtered hot, acidified with 35 ml. concentrated hydrochloricacid and cooled to yield 12.1 g. (47%) crystalline (+)-2'-chlorotartranilic acid. Recrystallization from water gave analyticalmaterial, M.P. 180.5-182.5, +994 (c.=1.65, 95% ethanol).

Analysis.Calc'd for C I-I ClNO C, 46.26; H, 3.88; N, 5.40. Found: C,46.22; H, 3.48; N, 5.32.

Example 5 -4'-chlorotartranilic acid.-( -2,3-diacetoxysuccinic anhydride(22 g., 0.1 mole) and 4-chloroaniline (15 g., 0.12 mole) in 150 ml.methylene chloride were stirred together for one hour. This solution wastreated with a solution of potassium hydroxide (21 g., 86% pellets, 0.32mole) in 50 ml. water. This two-phase system was stirred vigorously forone hour. The layers were separated and the Organic layer extracted with100 ml. water. The combined aqueous layers were heated to drive off anyresidual methylene chloride, filtered and acidified with ml.concentrated hydrochloric acid. After cooling, the crystals werecollected to give 24.2 g. (90%) (+)-4'- chlorotratranilic acid.Recrystallization twice from 3:1 Water:ethanol gave an analyticalsample, M.P. 193.0- 195.0, [M +18.9 (c.=1.64, 95% ethanol).

Analysis.--Calcd for C H CINO C, 46.26; H, 3.88; N, 5.40. Found: C,46.65, 46.62; H, 4.04, 4.05; N, 5.34.

Example 6 )-4'-bromotartranilic acid hydrate.( -2,3-diacetoxysuccinicanhydride (21.6 g., 0.1 mole) and 4-bromoaniline (17.2 g., 0.1 mole)were placed with 200 ml. methylene chloride and heated under reflux for3 hours. This solution was treated with a solution of potassiumhydroxide (21 g., 86% pellets, 0.32 mole) in 200 ml. water and stirredvigorously for ten minutes. The methylene chloride layer was separatedand extracted with 100 ml. water. The combined aqueous layers werestirred for two hours, warmed, filtered and acidified to give 20.5 g.(67%) crystalline (+)-4-bromotartranilic acid hydrate. This wasrecrystallized from ethanol-water with a decolorizing carbon treatmentto give 15 g. analytically pure (+)-4-bromotartranilic acid hydrate,M.P. 198.5- 201.5, [111 +90.5 (c.=l.8, 95% ethanol).

Analysis.--Calcd for C H BrNO -H O: C, 37.28; H, 3.76; N, 4.35; H O,5.59. Found: C, 37.07; H, 3.61; N, 4.32; E 0, 5.68.

Example 7.Reso1ution of(i)-6,7-dimethoxy-1-fl-hydroxyethyl-Z-methyl-1,2,3,4-tetrahydroisoquinolineCHSO NCI-Ia isomer isomer CHZCIIZOII To a warm solution of 73.1 g.(0.292 mole) of (1 6,7dimethoxy-1-fl-hydroxyethyl-Z-methyl-1,2,3,4-tetrahydroisoquinoline in375 ml. of 95 ethanol was added a warm solution of 39.4 g. (0.146 mole)of (+)-2'-nitrotartranilic acid in 375 ml. of 95% ethanol. The crystals(75.9 g.) were collected after storage at 5 C. for 20 hours. Onerecrystallization from 750 ml. of ethanol gave 69.8 g. (92%) ofmaterial, M.P. 193.5195.5.

This material was converted to its free base by neutralization withaqueous sodium carbonate and extraction with ethyl acetate.Concentration of the ethyl acetate extracts gave 30.0 g. of oil. Thisoil gave a crystalline hydrochloride from isopropanol and 10 ml. ofconcentrated hydrochloric acid. One recrystallization from 150 ml. ofabsolute ethanol gave 22.3 g. (55%) of (+)-6,7- dimethoxy 1 [3hydroxyethyl-Z-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, M.P.177180 [04],; +22.7 (c.=2.05, chloroform).

AHLIIYSiSr-CEICd for C14H21NO3HC11 C, H, 7.71; N, 4.87. Found: C, 58.67;H, 7.81; N, 4.63.

The mother liquor from the original crystallization was concentrated toMs its original volume, and treated with 1.0 g. (+)-2-nitrotartranilicacid in 25 ml. of ethanol. The solution was concentrated to dryness andthe resultant oil taken up in ethyl acetate, filtered, washed withaqueous sodium carbonate, dried over anhydrous sodium sulfate, andconcentrated to dryness to give 33.6 g. of an oil. This oil gave acrystalline hydrochloride from acetone-dry hydrogen chloride. Onerecrystallization from 95 ethanol gave 24.4 g. (60%) of()-6,7-dimethoxy- 1 18hydroxyethyl2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, M.P.177179, 22.8 (c.=2.02, chloroform).

Analysis.Calcd for C H NO -HCl: C, 58.43; H, 7.71; N, 4.87. Found: C,58.41; H, 7.81; N, 4.67.

Example 8 [2,l-a]azetidino-6,7-dimethoxy-Z-methyl-1,2,3,4-tetrahydroisoquinolinium p bromobenzenesulfonate.- 6,7 dimethoxy 2methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (23.8 g., 0.083mole) was converted to its free base by neutralization with sodiumcarbonate and extraction with 200 ml. chloroform. The chloroform extractwas dried over sodium sulfate and filtered. This solution was thentreated with 23.2 g. (0.091 mole) of p-bromobenzenesulfonyl chloride andstirred for four hours at room temperature. Anhydrous sodium carbonate(44 g.) was then added and stirring was continued sixteen hours. Thereaction mixture was filtered and the filtrate concentrated to give 38g. of crude crystalline material. One recrystallization from isopropanolgave 26.8 g. (69%) of analytical material, M.P. 178480, [a] 115.7(c.=2.02, chloroform).

Analysis.-Calcd for C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C,51.24; H, 5.24; N, 2.85.

Example 9 [2,l-a]azetidinc-6,7-dimethoxy-Z-methyl-1,2,3,4-tetrahydroisoquinolinium p bro1nobenzenesulfonate.6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride(22.6 g., 0.079 mole) was converted to its free base by neutralizationwith sodium carbonate and extraction with 200 ml. chloroform. Thechloroform extract was dried over sodium sulfate and filtered. Thissolution was then treated with 21.8 g. (0.085 mole) ofp-bromobenzenesulfonyl chloride and stirred for four hours at roomtemperature. Anhydrous sodium carbonate (41.5 g.) was added and stirringwas continued for sixteen hours. The reaction mixture was filtered andthe 23 filtrate concentrated to give 39 g. of crude crystallinematerial. One recrystallization from isopropanol gave 26.0 g. (70.3%) ofanalytical material, M.P. 179.5- 180.5", +114.2 (c.=2.00, chloroform).

Analysis.Calcd for C H BrNO S: C, 51.07; H, 5.14; N, 2.98. Found: C,51.11; H, 5.12; N, 2.75.

Example (+)-6,7-dimethoxy-1-B-(N-propionyl 3,4dichloroanilino)ethyl-2-methyl 1,2,3,4 tetrahydroisoquinolinefumarate.To a stirred solution of 2.4 g. (0.01 mole) 3,4-dichloropropionylanilide in 35 ml. of dried dimethylformamide maintainedunder a nitrogen atmosphere was added 0.47 g. of a 58.6% dispersion ofsodium hydride in mineral oil. After minutes, 4.7 g. (0.01 mole)(+)-[2,l-a] azetidino-6,7-dimethoxy-2-methyl 1,2,3,4tetrahydroisoquinolinium p bromobenzenesulfonate was added, and stirringwas continued for 16 hours at room temperature.

The dimethylformamide was removed by concentration under reducedpressure to give a residue. The residue was suspended in 50 ml. water-5Oml. ethanol. The layers were separated and the aqueous layer extractedtwice with 50 ml. portions of ethyl acetate. The combined ethyl acetateextracts were dried over Na SO filtered, and concentrated. The resultantoil was taken up in acetonitrile and Washed with n-pentane to removemineral oil. The acetonitrile solution was concentrated to give 4.5 g.of an almost clear oil. The oil in 25 ml. of hot propanol was added to asolution of 1.13 g. fumaric acid in 25 ml. hot isopropanol. Theresulting solution was cooled to room temperature, seeded, and stored at5 C. The fumarate salt crystallized upon standing. Recrystallizationfrom isopropanol yielded 3.3 g. (+)-6,7-dimethoxy-l-8-(N-propionyl-3,4-dichloroanilino)ethyl-Z-methyl 1,2,3,4tetrahydroisoquinoline fumarate, M.P. 132.5-134 0., [M 27.5 (c.:=2.0,chloroform).

Analysis -CZICd for C23H23Cl2N203 C4H404: C, 57.14; H, 5.70; N, 4.94.Found: C, 57.12; H, 5.58; N, 4.83.

This is the (R) isomer in the nomenclature of Cahn, Ingold and Prelog,Experientia, XII (3), 81-94 (Mar 15, 1956). All or virtually all of theanalgesic activity resides in this (R) isomer, whether it is in the formof the free base or an acid addition salt.

Example 11 (-)-6,7-dimethoxy-1-B-(N-propionyl 3,4dichloroanilino)ethyl-2-methyl 1,2,3,4 tetrahydroisoquinolinefumarate.To a stirred solution of 2.4 g. (0.01 mole) 3,4-dichloropropionylanilide in ml. of dried dimethylformamide maintainedunder a nitrogen atmosphere was added 0.47 g. of a 5 8.6% dispersion ofsodium hydride in mineral oil. After 15 minutes, 4.7 g. (0.01 mole)()-[2,1-a1azetidino-6,7-dimethoxy-Z-methyl l,2,3,4tetrahydroisoquinolinium p bromobenzenesulfonate was added, and stirringwas continued for 16 hours at room temperature.

The dimethylformamide was removed by concentration under reducedpressure to give a residue. The residue was suspended in 50 ml. water-50ml. ethanol. The layers were separated and the aqueous layer wasextracted twice with 25-50 ml. portions of ethyl acetate. The combinedethyl acetate extracts were dried over Na SO filtered, and concentrated.The resultant oil was taken up in acetonitrile and washed with n-pentaneto remove mineral oil. The acetonitrile solution was concentrated togive 4.4 g. of a light yellow oil. The oil in 25 ml. of hot isopropanolwas added to a solution of 1.13 g. fumaric acid in 25 ml. hotisopropanol. The resulting solution was cooled to room temperature,seeded, and stored at 5 C. The fumarate salt crystallized upon standing.Recrystallization from isopropanol yielded 2.70 g.()-6,7-dimethoxy-1-fi-(N-propionyl-3,4-dichloroanilino)ethyI-Z-methyl1,2,3,4 tetrahydroisoquinoline fumarate, M.P. 132.5134.0 C., +27.5(cl-:20, chloroform).

Analysis.Calcd for C23H2 Cl2N203 C4H4041 C, 57.14; H, 5.70; N, 4.94.Found: C, 57.06; H, 5.89; N, 4.96.

This is the (S) isomer in the nomenclature of Cahn, Ingold and Prelog,Experientia, XII (3), 81-94 (Mar. 15, 1956).

The compounds of this invention may be administered as the free bases orin the form of their nontoxic addition salts. They may be compounded andformulated into pharmaceutical preparations in unit dosage form for oralor parenteral administration with organic or inorganic solid materialsor liquids which are pharmaceutically acceptable carriers. Thecompositions may take the form of tablets, powders, granules, capsules,suspensions, solutions and the like. Such compositions are consideredwithin the scope of this invention.

The compounds of this invention when administered orally or parenterallyin an effective amount are effective in the treatment of pain.

While this invention has been described and exemplified in terms of itspreferred embodiment, those skilled in the art will appreciate thatmodifications can be made without departing from the spirit and scope ofthis invention.

What is claimed is:

1. A member selected from the group consisting of compounds of theformula OHSO N-CHa wherein Ar is a member selected from the groupconsisting ing of hydrogen, (lower)alkyl, (lower)alkanoyl,cyclopropylcarbonyl, (lower) alkylsulfonyl and wherein R and R are eacha member selected from the group consisting of hydrogen, chloro, bromo,fluoro, trifiuoromethyl, methyl, ethyl, methoxy, and ethoxy; andnontoxic pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 having the formula CHaO I Y C H O 113-17!-wherein X and Y are each a member selected from the group consisting ofhydrogen, chloro, bromo, fluoro, trifluoromethyl, methyl, ethyl, methoxyand cthoxy; and wherein R is a member selected from the group consistingof hydrogen, (lower) alkyl, (lower)alkanoyl, cyclopropylcarbonyl,(lower) alkylsulfonyl and CHaO orno

- Y CH2CH3-N wherein R is (lower)-alkanoyl; X and Y are each a memberselected from the group consisting of hydrogen, chloro, bromo, fluoro,trifluoromethyl, methyl, ethyl, methoxy and ethoxy :and nontoxicpharmaceutically acceptable acid addition salts thereof.

4. A compound of claim 1 having the formula cmo omo 2:

wherein R is (lower)a1kylsulfonyl; X and Y are each a member selectedfrom the group consisting of hydrogen, chloro, bromo, fluoro,trifluoromethyl, methyl, ethyl, methoxy and ethoxy and nontoxicpharmaceutically acceptable acid addition salts thereof.

5. A compound of claim 1 having the formula C1130 CH3 X Y t..c..

wherein R is hydrogen; and X and Y are each a member selected from thegroup consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl,methyl, ethyl, methoxy, and ethoxy and nontoxic pharmaceuticallyacceptable acid addition salts thereof.

6. A compound of claim 1 having the formula CHaO -CH3 CH O X HzGHr-III-wherein R is cyclopropylcarbonyl; X and Y are each a member selectedfrom the group consisting of hydrogen, chloro, bromo, fluoro,trifluoromethyl, methyl, ethyl, methoxy and ethoxy; and nontoxicpharmaceutically acceptable acid addition salts thereof.

7. A compound of claim 1 having the formula omo X Y wherein R is(1ower)alky1; X and Y are each a member selected from the groupconsisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl, methyl,ethyl, methoxy and ethoxy; and nontoxic pharmaceutically acceptable acidaddition salts thereof.

8. A compound of claim 1 having the formula CHaO c1130 NAJH c1 andnontoxic pharmaceutically acceptable acid addition salts thereof.

9. A compound of claim '1 having the formula 01330 N"OH3 Hr cmcm-tw-C?=o and nontoxic pharmaceutically acceptable acid addition salts thereof.

10. A compound of claim 1 having the formula orno orno 0 F3 r 1 on,

and nontoxic pharmaceutically acceptable acid addition salts thereof.

11. A compound of claim 1 having the formula CHaO C1130 N-C H3 F tmflathe F CH3 and nontoxic pharmaceutically acceptable acid addition saltsthereof.

12. A compound of claim 1 having the formula N-CH;

and nontoxic pharmaceutically acceptable acid addition salts thereof.

and nontoxic pharmaceutically acceptable acid addition salts thereof.

14. A compound of claim 1 having the formula CHaO CHKO N-CHs C1 01 H CHIII- 2 i and nontoxic pharmaceutically acceptable acid addition saltsthereof.

15. A compound of claim 1 having the formula C1130 N CH3 omCHzCI-Iz-NII- and nontoxic pharmaceutically acceptable acid additionsalts thereof.

16. A compound of claim 1 having the formula CHaO- N--C II; 0 H3 andnontoxic pharmaceutically acceptable acid addition salts thereof.

17. The compound of claim 1 having the formula CHsO CHQO NCH3(EHiCH1-1YT-Cl G1 I CH3 and nontoxic pharmaceutically acceptable acidaddition salts thereof.

18. The compound of claim 1 having the formula CHaO NCH3 I and nontoxicpharmaceutically acceptable acid addition salts thereof.

19. The compound of claim 1 having the formula and nontoxicpharmaceutically acceptable acid addition salts thereof.

20. The compound of claim 1 having the formula NOH and nontoxicpharmaceutically acceptable acid addition salts thereof.

21. The (R) isomer of the compound of claim 17.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

D. G. DAUS, Assistant Examiner.

